Medicinal delivery system and related methods

ABSTRACT

A method is provided of making a medicinal delivery system which satiates a craving in an individual when the medicinal delivery system is administered orally to the individual. A coating composition is applied on a saliva-soluble powder to establish a coated powder, the coating composition featuring an at least partially solubilized craving satiation medicinal compound. The coated powder is combined with an edible carrier base to establish a medicinal delivery system that rapidly releases medicine and buffer preferably followed by slower, sustained release.

CROSS REFERENCE TO RELATED APPLICATION AND CLAIM TO PRIORITY

This application is a division of application Ser. No. 11/878,163 filedJul. 20, 2007, now U.S. Pat. No. 8,642,016, which is based onprovisional application Ser. No. 60/832,127, filed Jul. 21, 2006, forJohn M. Pinney et al., the disclosures of which are is incorporatedherein by reference and to which priority is claimed under 35 U.S.C. §119(e).

FIELD OF THE INVENTION

Embodiments of the invention relate to a medicinal delivery systemcontaining an edible carrier such as a chewing gum or lozenge, and anactive ingredient present in sufficient amount and releasable at asufficient rate to satiate and relieve a craving. Other embodimentsrelate to methods of making the medicinal delivery system, and methodsof administering the medicinal delivery system to an individual in needof satiation of and relief from a craving. In preferred embodiments, themedicinal delivery system includes a nicotine active ingredient forsatiation of and relief from smoking cravings due to nicotinewithdrawal.

BACKGROUND OF THE INVENTION

Nicotine is a highly addictive chemical present in cigarettes and othertobacco products, including smokeless tobacco products. Cigarettes arebroadly considered the prototypic form of the most addictive and harmfultype of tobacco product, however, addiction can develop to all presentlyknown types of nicotine containing tobacco products, and all can beharmful. Therefore, although “cigarettes” and “smoking” are discussedthroughout this disclosure, the principles and application of theresulting medicinal formulation apply to all forms of tobacco use andaddiction.

Most cigarette smokers find achieving and maintaining prolonged smokingabstinence to be difficult. Research has indicated that abstainingsmokers experience periodic and episodic peaks or surges of chroniccraving, typically evoked by internal or external stimuli. Personsattempting to quit cigarette smoking often fail in their attempts andsuffer from relapse due to the overwhelming intensity of these episodiccraving peaks. There is, therefore, a need to provide a cigarettesubstitute which satiates these episodic craving peaks before relapsecan occur.

Some acute treatments for countering cravings are behavioral. As anexample, it is often recommended that smokers eat or chew something todistract their attention from their nicotine craving. Many smokers findthese behavioral treatments ineffective. Also, these behavioraltreatments can lead to the development of other problems, such as weightgain due to constant eating.

It has also been proposed that the administration of acute doses ofnicotine could satisfy cravings, much in the manner that smoking acigarette satiates a nicotine-withdrawal craving. Nicotine deliverysystems containing actives for oral administration now include variouschewing gum and lozenge formulations. Chewing gums permit release ofnicotine over time as the gum product is masticated, or chewed. Theaction of saliva on the gum or lozenge upon ingestion furtherfacilitates release of nicotine, as well as its subsequent absorption bythe mucous membranes lining the mouth, throat, larynx and esophagus.

Nicotine is a weak base with a pKa of approximately 8.0. Absorption ofnicotine into the bloodstream from the oral mucosa is highly dependentupon the concentration of un-ionized nicotine. Only un-ionized nicotinecan be absorbed through the oral mucosa. Ionized nicotine cannot beabsorbed and will be swallowed and mostly lost during transit throughthe gastrointestinal tract. Efficient mucosal absorption of nicotine maybe facilitated by addition of a buffer to the gum to convert ionizednicotine to un-ionized nicotine. For example, without buffer, at anormal saliva pH of 6.5, only 3% of the available nicotine is in theun-ionized form which can be absorbed, whereas, at a buffered saliva pHof 9.0, approximately 91% of the available nicotine is in an un-ionizedstate which can be absorbed transmucosally. Buffer and nicotineincorporated into gum are released at the same time during chewing. Aneffective buffer raises the pH of saliva from a pH of approximately 6-7to a pH of approximately 8-11. The buffer converts ionized nicotine toun-ionized nicotine that can be absorbed into the bloodstream. Thus,efficient delivery of nicotine to the bloodstream is a function of theefficiency of nicotine release and the efficiency of buffer to convertionized nicotine to un-ionized nicotine.

A commercially available nicotine delivery gum is marketed under thetrademark NICORETTE®. This commercially available gum utilizes the “chewand park” method for providing nicotine release. The consumer bites downon a piece of gum until sensing a “tingle”, then parks the gum insidethe mouth for a period, and then repeats this regimen to obtain furtherrelease of nicotine. Nicotine is released in a steady, slow manner, andthus is highly dependent on conscious chewing actions by the user.

Nicotine released from NICORETTE reaches the bloodstream in severaldifferent ways. About 50% of the nicotine from the 2 and 4 milligramversions of NICORETTE is released from the gum during chewing. The restof the nicotine typically remains in the gum and is discarded by theuser. Of the nicotine delivered by the 2 milligram version of theNICORETTE gum to the saliva, about 0.8 milligram may be absorbed throughthe membranes of the mouth (the buccal mucosa) and appear in thebloodstream. The remaining approximately 0.2 milligram is swallowed, ofwhich 0.06 milligram survives the first pass effects of hepaticmetabolism and appears in the bloodstream. The 4 milligram version ofNICORETTE gum achieves nicotine absorption values which areapproximately twice those of the 2 milligram version.

Because of slow nicotine release and weak buffering action, it takesapproximately 10 to 30 minutes after ingestion to achieve adequate bloodlevels of nicotine from NICORETTE, regardless of whether the userpractices the “chew and park” (or “bite and park”) method or chews atregular intervals (e.g., one chew per 4 seconds) to relieve cravings.Although the amount of nicotine absorption from NICORETTE is related tothe chewing rate and the time the saliva is held in the mouth, thesevariables are significant only at the extremes of rapid versus slowchewing action, and frequent versus infrequent swallowing. Outside ofsuch extremes, these variables have very little impact on nicotineabsorption.

The critical period of delay immediately following the onset of acraving, i.e., during the episodic craving peak or event, is the timethe smoker experiencing a craving would normally choose to smoke acigarette to access nicotine for relieving the craving. A product thatdelivers nicotine too slowly will be ineffective in relieving orsatisfying the episodic craving peak or event. For example, in the caseof NICORETTE, a delay of 10 minutes or more in the release andabsorption of a nicotine dose comparable to the amount of nicotinederived from a cigarette may be excessively long to wait for someone whois trying to quit smoking. In practice, most commercial products simplyfail to deliver an adequate dosing of the medication, especially earlyin the administration process, i.e., within a few minutes ofadministration. The result many times is a product that the smokingcustomer seeking to abstain from smoking finds highly ineffective insatiating his or her cravings. As a consequence, the smoker will succumbto the craving by turning to a cigarette before the medicinal nicotinedelivery system has released adequate nicotine to satiate the craving.

There is consequently a need in the art for an improved delivery systemfor actives such as nicotine. More specifically, there is a need for animproved medicinal delivery system that provides a rapid release ratefor nicotine or other medicines early in the ingestion (e.g., chewing)process, together with adequate buffering, to simulate the nicotinerelease of a cigarette and quench the craving of the abstaining smoker.Following an initial phase of rapid release, there is preferably asustained release of medicine. The rapid release of medicine followed bya sustained release is referred to herein as “bi-phasic release”. Thereis a need in the art for a nicotine delivery product which is highlyefficacious in releasing a specified, effective quantity of the activeingredient shortly after administration to provide the user withadequate blood levels of nicotine soon after onset of ingestion forsuppression of cravings and withdrawal symptoms followed by sustainedrelease of some or all of the remaining dose.

A rapid achievement of adequate blood levels of nicotine, preferablyover the first five minutes of oral manipulation (e.g., chewing) wouldmove the product toward a closer approximation of the nicotine bloodlevels delivered by smoking a cigarette. With a formulation that rapidlyreleases amounts of nicotine and buffer, preferably over the first fiveminutes of oral manipulation in a form that is readily absorbed into thebloodstream, the smoker can satiate and obtain relief from cravingsquickly, before episodic craving peaks or events drive the smoker intorelapse.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, a method is provided ofmaking a medicinal delivery system that delivers medicine which satiatesa craving in an individual experiencing nicotine withdrawal when themedicinal delivery system is administered orally to and orallymanipulated by the individual. The method features applying a coatingcomposition on a saliva-soluble powder to establish a coated powder, thecoating composition comprising an at least partially solubilizedcraving-satiation medicinal compound, and combining the coated powderwith an edible carrier base, such as a chewing gum or lozenge base, andbuffer to establish a medicinal delivery system.

A second aspect of the invention provides a method of satiating acraving in an individual, in which a medicinal delivery system isadministered to an individual in need of a craving satiation. Themedicinal delivery system is made by applying a coating composition on asaliva-soluble powder to establish a coated powder, and combining thecoated powder with a carrier base, such as a chewing gum or lozengebase, and buffer to establish the medicinal delivery system. The coatingcomposition features an at least partially solubilized craving satiationmedicinal compound.

According to a third aspect of the invention, a medicinal deliverysystem is provided. The system features an edible carrier, such as achewing gum or lozenge base, a buffer, and a saliva-soluble powdercoated with a craving-satiation compound. In a preferred embodiment, thecraving-satiation compound comprises nicotine.

A fourth aspect of the invention provides a method of making anicotine-satiation delivery system which satiates smoking cravings in anindividual in need of nicotine-craving relief when thenicotine-satiation delivery system is administered orally to and orallymanipulated (e.g., masticated) by the individual. The method featuresapplying a coating composition on a saliva-soluble powder, and combiningthe coated powder with an edible carrier base, such as a chewing gum orlozenge base, and buffer to establish the nicotine-satiation deliverysystem. The coating composition features an at least partiallysolubilized nicotine compound.

According to a fifth aspect of the invention, a method is provided ofsatiating a smoking craving in an individual, comprising administering amedicinal delivery system to an individual in need of a smoking-cravingrelief, for example, a person practicing abstinence from smoking. Themedicinal delivery system is made by applying a coating composition on asaliva-soluble powder, and combining the coated powder with an ediblebase, such as a chewing gum or lozenge base. The composition features anat least partially solubilized nicotine compound.

In preferred yet optional embodiments of the above-described aspects ofthe invention, the coated powder and the buffer system are substantiallyuniformly and homogenously distributed in the gum or lozenge base, forexample, by thorough mixing, for rapid release along with nicotine.

In preferred embodiments of the above-described aspects, rapid releaseof medicine is obtained over the first five minutes following the onsetof ingestion, e.g., mastication, of the medicinal delivery system,optionally yet preferably followed by a less rapid sustained release ofmedicine over a 5-20 minute, more preferably a 10-20 minute period. Thispattern of release is referred to as bi-phasic release of medication.The product rapidly releases buffer over the first five minutes, thusfacilitating rapid absorption of medication. The combination of rapidrelease of medicine and buffer followed by sustained release insuresrapid absorption of the medicine and rapid and sustained relief ofcraving.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are incorporated in and constitute a part ofthe specification. The drawings, together with the general descriptiongiven above and the detailed description of the preferred embodimentsand methods given below, serve to explain the principles of theinvention. In such drawings:

FIG. 1 is a flow diagram of a method of making medicinal delivery systemaccording to an embodiment of the invention;

FIGS. 2 through 4 are graphs showing the nicotine release rates ofseveral examples and comparative examples; and

FIGS. 5 and 6 are graphs showing mean plasma nicotine concentrationplots of several examples and for NICORETTE FreshMint (4 mg) chewinggum, with baseline adjusted levels shown in dashed lines.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Reference will now be made in detail to the presently preferredembodiments and methods of the invention as illustrated in theaccompanying drawings. It should be noted, however, that the inventionin its broader aspects is not limited to the specific details,representative devices and methods, and illustrative examples shown anddescribed in this section in connection with the preferred embodimentsand methods. The invention according to its various aspects isparticularly pointed out and distinctly claimed in the attached claimsread in view of this specification, and appropriate equivalents.

Unless otherwise stated, all percentages provided herein are weightpercentages, based on the total weight of the medicinal deliverycomposition, except where noted otherwise.

A method of making a medicated and buffered delivery system for cravingsatiation according to an embodiment of the invention is now describedin detail with reference to FIG. 1. At least one craving-satiationcompound is at least partially dissolved in a suitable solvent orsolvents. As referred to herein, the phrase “at least partiallydissolved” should be understood to encompass dissolution (also referredto as solubilization) of the craving-satiation compound in a solvent,and may encompass formation of a free-flowing liquid or a semi-liquid,such as a suspension, emulsion, or paste. The phrase “at leastpartially” also encompasses complete dissolution of thecraving-reduction compound.

The particular solvent selected will depend upon its ability to dissolvethe craving-satiation compound and its compatibility with the process.Polar solvents such as water and lower alkanols (e.g., ethanol) areparticularly preferred for solubilizing nicotine. A solubilized bulksweetener solution, especially a sugar alcohol such as a sorbitolsolution, is especially preferred for partially dissolving thecraving-satiation medicinal compound into a paste. In the event bulksweeteners are selected as the saliva-soluble powder and for the solventsolution, the bulk sweetener in the solvent solution may be the same asor different from the bulk sweetener selected as the saliva-solublepowder.

At least one bulk sweetener preferably is highly soluble in water.Optionally, additional bulk sweeteners having moderate or low solubilityin water may also be included in the premix. The high solubility isdesired so that the selected bulk sweetener(s) will dissolve quickly inthe mouth of the recipient upon mastication of the chewing gum orabsorption (e.g., via sucking) of the lozenge, releasing the medicinalcraving-satiating compound applied as a coating to the powder of thepremix. The following solubility data for sugar alcohols is reported bySchiwek, H. in Ullman's Encyclopedia of Industrial Chemistry, 5^(th) ed.Vol. A25, Sugar Alcohols, (1994). It is preferred that the sugar alcoholsolution, if selected, be selected from a sugar alcohol having asolubility of at least 50, more preferably at least about 65, and stillmore preferably at least about 70 grams of sugar alcohol dissolved per100 grams of water.

TABLE 1 Solubility (grams/100 Sugar Alcohol grams water) Mannitol 23Isomalt 38 Lactitol 55 Maltitol 71 Xylitol 70 Sorbitol 75

The solubilized craving-satiation compound is then coated onto asaliva-soluble powder. Coating may be performed at room temperature.Standard coating equipment and procedures may be employed for coatingthe craving-satiation compound on the powder. The coated saliva-solublepowder is also referred to herein as a “premix.” It should be understoodthat the premix may contain additional ingredients, although any suchadditional ingredients preferably will not adversely affect the coatingof the active onto the saliva-soluble powder. Preferably, the premix isfree of components that are insoluble in saliva. The solvent optionallymay be removed, such as by evaporation or otherwise, before or morepreferably after the active has been coated on the powder. The entireprocess of complete or partial dissolution of a craving-satiationcompound in a solvent, coating onto a saliva-soluble powder, and solventremoval to form the “pre-mix” is herein referred to as “solventtreatment”.

Without wishing to be bound by any theory, it is believed that the“solvent treatment” of nicotine during preparation of the premix altersthe crystalline form of the nicotine to either another crystalline formor, more likely, to an amorphous state which is more readilysolubilizable during ingestion to promote a high initial nicotinerelease rate. Again not wishing to be bound by theory, it is furtherbelieved that coating the nicotine on a saliva-soluble, water-solublepowder such as sorbitol improves the rapid release of the nicotine,thereby increasing performance of the delivery system. Dissolution ofthe powder during mastication or other ingestion creates a liquid mediumthat can entrain and wash out the nicotine and buffer from the gum orlozenge rapidly. The nicotine becomes available for absorption by theuser more quickly in this manner. As discussed below, the rapidavailability of the nicotine makes possible nicotine release rates ofgreater than 45 and even 50 weight percent within 5 minutes of the onsetof oral ingestion.

The premix is combined with an edible carrier, such as a gum base orlozenge base, and optionally additional ingredients. The procedures setforth in U.S. Pat. No. 4,405,647 may be especially helpful to theskilled artisan as general guidance for the preparation of the chewinggum delivery system. Briefly stated, the gum base material may be meltedor softened using one or more of the softening agents, plasticizersand/or solvents and filler materials. The premix and additionalingredients, such as buffering agents and others described below, arethen admixed into the carrier base. The premix may be added to thecarrier base at any time during the mixing procedure, including towardsthe end of the mixing procedures, e.g., after the carrier base materialhas been mixed with the other components. It is preferred, yet optional,however, that after the addition of the premix sufficient mixing beperformed to distribute the premix coated powder substantiallyhomogenously. It should be understood that the pre-mix, carrier base,and additional ingredients may be combined with one another in anysequence.

Mixing optionally is accomplished by comminuting the gum base materialtogether with the water-soluble ingredients in a bed or blender within agaseous medium at room temperature, as described in the aforementionedU.S. Pat. No. 4,405,647. This material is continuously pulverized andthereby chopped into much smaller particles. To prevent adherence of theresultant particles to one another, additional filler or bulkingmaterial may be added like lubricants, glidants and other tableting andcompression aids well known in the pharmaceutical industry, such as forexample, silica gel or calcium carbonate. Granules of any desired sizeand shape may be obtained upon the introduction of a standard meshscreen to separate the particulates once formed.

Medicinal Craving-Satiation Compound

The terms medicinal and medicine as used herein are not limited tosubstances which relieve pain, disease and/or infection. The termsencompass therapeutic substances which can be effectively incorporatedinto the medicine-delivery system to satiate cravings of the recipient.

The medicinal craving-satiation compound preferably comprises a solubletobacco alkaloid. Tobacco alkaloids include nicotine and nicotine-likeor related pharmacologically active compounds such as nor-nicotine,lobeline and the like, as well as the free base substance nicotine andall pharmacologically acceptable salts of nicotine, including acidaddition salts. “Nicotine compounds” as that term is used hereintherefore includes all the foregoing tobacco alkaloids. Of these, thenicotine salts are useful and can include, for example, nicotinehydrogen tartrate and nicotine bitartrate dihydrate (NBD), as well asnicotine hydrochloride, nicotine dihydrochloride, nicotine sulfate,nicotine citrate, nicotine zinc chloride monohydrate and nicotinesalicylate, nicotine polacrilex, and other nicotine-ion exchange resins,either alone or in combination. Of the foregoing, nicotine hydrogentartrate and nicotine bitartrate dihydrate may be especially suitable.

A serving of the composition of the invention preferably contains about0.1 to about 10 milligrams of nicotine (as measured in its free baseform) or other craving satiation medicinal compound. More desirably, theamount of nicotine will be within the range of about 1.0 to about 5.0milligrams, for example in standard dosing units of approximately 2milligrams and 4 milligrams. As a weight percentage, nicotine (inwhatever chosen form, measured as per its free base form) desirablyconstitutes about 0.1 to about 1.0 weight percent, more preferably about0.1 to about 0.5 weight percent of the total weight of the medicinaldelivery system composition. In the premix, the nicotine preferablyconstitutes about 1.0 to about 20 weight percent of the total weight ofthe premix composition. It has been found that a relatively uniformcoating of craving-satiation medicinal compound may be obtained on thesaliva-soluble powder by practicing the above ranges.

The concentration of active in the composition may be selected toprovide an intended dosage or release rate. The desired dosage ofnicotine (or other active) selected may depend upon the nature andseverity of the craving to be treated, the treatment regime,characteristics (e.g., weight, age, gender) of the recipient, and otherfactors affecting treatment. Selection of an appropriate activeconcentration may also take into consideration the particularingredients selected, such as the potency of the nicotine source orother active utilized, and the nature and amount of solvent.

Additionally, it is contemplated that the skilled artisan may choose toadd extra or secondary active, e.g., not contained in the premix butadded to the carrier base. The secondary active preferably constitutesno more than about 25 percent of the system total weight. The amount inexcess of approximately 10 weight percent may be regarded as overage,that is, the amount which may be expected to be “washed away” orotherwise not released or absorbed during ingestion. An example of asecondary nicotine source is a solid complex of one or more tobaccoalkaloid compounds bound to an ion exchange resin or other polymerrelease system, particularly a cation exchanger. The inclusion of someion-exchange resin in the formulation may further act synergistically onthe nicotine release rate for the nicotine salts. An exhaustive listingof nicotine ion exchange resins and their chemistry is readily availablefrom various sources in the industry, and the skilled artisan mayconsult Lichtneckert et al., U.S. Pat. No. 3,901,248, for a furtherdiscussion and listing of resins. Nicotine polacrilex as a nicotine ionexchange resin may be especially desirable for use with the composition.

Saliva-Soluble Powder

The saliva-soluble powder is preferably water-soluble and morepreferably contains at least one bulk sweetener. Generally, bulksweeteners impart improved palatability to the composition, and therebyprovide a pleasant chewing experience to help in masking the bitter,acrid taste of nicotine. The “sweetener” may or may not be perceptiblysweet. Examples of sweeteners include those compounds selected from thegroup consisting of saccharide material such as the mono-, di-, tri- andpolysaccharide materials available in the industry, including oligomers,and oligosaccharides. As non-limiting examples, sugars such as sucrose,glucose (corn syrup), dextrose, invert sugar, fructose, and mixturesthereof may be useful. Less or non-sweet sugars and polysaccharidematerials such as maltodextrin and polydextrose may also be utilized.For certain individuals, such as those concerned about weight gain andtooth decay, “sugar-free” or “non-sucrose” formulations may beespecially desirable. Thus, natural and synthetic non-saccharide-basedbulk sweeteners may be selected from the group consisting of saccharinand its various salts such as the sodium and calcium salts, cyclamicacid and its various salts, dipeptide sweeteners, chlorinated sugarderivatives such as sucralose, dihydrochalcone, glycyrrhin, Steviarebaudiana (Stevioside), and sugar alcohols such as sorbitol, sorbitolsyrup, mannitol, xylitol, hexa-resorcinol and the like, includingmixtures of any of the foregoing, are contemplated for use herein.Hydrogenated starch hydrolysate (lycasin), and the potassium, calciumand sodium salts of3,6-dihydro-6-methyl-1-1,2,3-oxathiazin-4-one-2,2-dioxide may also beincluded as sweetener material. Of the foregoing, sorbitol and xylitolare particularly preferred, either alone or more desirably incombination. Xylitol has been reported to possess non-cariogenic oranti-cariogenic properties.

The saliva-soluble powder preferably makes up about 70 to about 97weight percent of the premix. It should be understood that additionalsaliva-soluble powder, such as bulk sweeteners (e.g., sorbitol) may beadded to the medicate composition apart from the premix, e.g., by directaddition to the carrier base separate from the premix. It is preferredthat the total weight of bulk sweetener found in the composition be in arange of about 30 to about 60, more preferably about 40 to about 50weight percent of the total weight of the formulation.

Preferably, the saliva-soluble powder is in a fine form, for example,with particle sizes of 600 microns or less, and is in a substantiallynon-agglomerated state prior to receiving a coating in the premixpreparation stage.

Carrier Base

Suitable solid carrier bases include, but are not necessarily limitedto, chewing gum and lozenges.

Gum Base

The chewing gum comprises a gum base matrix as a major component. Thegum base matrix includes at least one gum base material which may beselected from the many water-insoluble and saliva-insoluble gum basematerials known in the art. Illustrative examples of suitable polymersfor gum bases include both natural and synthetic elastomers and rubbers,as well as mixtures thereof. Naturally-derived polymers include, forexample, substances of plant origin like chicle, jelutong, gutta perchaand crown gum. Synthetic elastomers such as butadiene-styrenecopolymers, isobutylene and isoprene copolymers (e.g., “butyl rubber” inthe art), polyethylene, polyisobutylene, polyvinylesters such aspolyvinylacetate, and mixtures of any of the foregoing may beparticularly useful.

In one embodiment, it is highly preferable that the gum base be selectedso as to provide a final chewing gum composition which has a relatively“soft” chew both at the onset of mastication, as well as towards the endof the chewing process, and even as long as about 20 to 30 minutes orso. Another desirable characteristic of the gum base should be itsability to achieve preferred results sought by the present invention,e.g., to facilitate the early release over the first 5 minutes of atleast 45 weight percent, more preferably at least 50 weight percent ofthe active ingredient(s), such as nicotine, as well as early release ofsufficient buffer (described below) to raise the pH of mouth saliva tothe range of pH 8-10.

In another preferred embodiment of the invention, the type of gum baseutilized includes at least some butyl rubber (copolymer of isoprene andisobutylene), with additional amounts of polyisobutylene, and withpolyvinylacetate (preferably PVA having a MW of approximately 12,000)also being present. This butyl-rubber based material appears to havecertain advantages when used together with nicotine in the form of asalt.

The gum base matrix will typically comprise from about 30 to about 90weight percent of the total weight of the chewing gum composition of theinvention. It is more preferred for the chewing gum base matrix materialto constitute less than about 70 percent of the total weight of thechewing gum composition. It is especially preferred for the gum basematrix to constitute from about 35 to about 55 weight percent of thechewing gum composition. Excess gum base may interfere with the releaseof the active tobacco alkaloid material, and additionally, maycontribute to tackiness and poor mouth-feel of the final product.

It is contemplated that about 25 weight percent to about 75 weightpercent, e.g., about 30 weight percent to about 60 weight percent, ofthe gum base matrix consists of the gum base polymer material(s)heretofore described. An exemplary gum base matrix formulation containspolyvinylacetate having a molecular weight of about 12,000 (about 14weight percent of the total chewing gum composition), polyisobutylene(about 5 weight percent of the total chewing gum composition), and butylrubber (about 4 weight percent of the total chewing gum composition).Together these polymers may comprise about 35 weight percent to about 45weight percent of the gum base matrix, e.g., about 40% of the gum basematrix.

The gum base matrix may additionally contain other ingredients wellknown, such as plasticizers, processing aids, and softeners to helpreduce the viscosity of the gum base to a desirable consistency and toimprove the overall texture and bite. These compounds are also noted fortheir emulsifying properties. As non-limiting examples, compounds suchas lecithin, mono- and diglycerides, lanolin, stearic acid, sodiumstearate, potassium stearate, glycerol triacetate, glycerol monostearateand glycerin are provided. Stearic acid, lecithin and mono- anddiglycerides are particularly exemplary. Plasticizers and softeners aredesirable as part of the formulation because in addition to softeningthe primary gum base polymeric compound, they also may facilitaterelease of the active upon mastication. When added, the plasticizers andsofteners may constitute, for example, from about 0.1 to about 20 weightpercent of the gum base matrix, and more desirably may constitute about5 weight percent to about 15 weight percent of the gum base matrix.

Waxes such as beeswax and microcrystalline wax, and fats/oils such assoybean and cottonseed oils are also contemplated as optionally part ofthe gum base formulation. These compounds also function as softeningagents. Typically, these compounds (either alone or in combination) maycomprise from zero up to about 25 weight percent of the gum base matrix,and even more desirably will constitute less than about 20 weightpercent of the gum base matrix, e.g., about 15 weight percent to about20 weight percent of the gum base matrix. An especially desirableformulation will include a combination of microcrystalline wax andpartially hydrogenated soybean oil in an approximate 1:2 weight ratio. Amore exhaustive listing of these compounds, along with recommendedweight percentages, may be found in available industry literature.

Softeners also may be included as part of the gum base matrix,especially softeners selected from the group consisting of rosin andresin material typically utilized in the confectionery chewing gumindustry. Examples include methyl, glycerol, and pentaerythritol estersof rosins or modified rosins, such as hydrogenated, dimerized orpolymerized rosins or mixtures thereof. More specific examples includepentaerythritol ester of partially hydrogenated wood rosin,pentaerythritol ester of wood rosin, glycerol ester of wood rosin,glycerol ester of partially dimerized rosin, glycerol ester ofpolymerized rosin, glycerol ester of tall oil rosin, glycerol ester ofwood rosin and partially hydrogenated wood rosin and partiallyhydrogenated methyl ester of rosin, such as polymers of alpha-pinene orbeta-pinene, and terpene resins including polyterpene and mixturesthereof. Elastomers can comprise from about zero to 75 weight percent ofthe gum base matrix. It is possible to minimize or even eliminate thequantity of rosin/resin in the gum base.

The gum base matrix may be material as heretofore described, i.e., thatwhich facilitates release of the active (as for example that having ahydrophilic moiety, or a butyl rubber-based moiety), or may be other gummatrix material known in the art. For example, a low-moisture,non-aqueous gum base matrix having a high degree of hydrophobicity maybe utilized in certain formulations. In certain situations, the gum basematrix material and the nicotine can have different, somewhatincompatible moieties so that the nicotine is not strongly retained bythe gum base matrix, and can be released more easily.

Lozenge Base

As mentioned above, another carrier useful for the present invention isa lozenge. Generally, lozenges are hard candy-like sources oftherapeutic compounds. Lozenges usually contain high levels ofsweeteners in the form of natural or synthetic sugar substitutes, suchas sucrose and corn syrup, or a sugar alcohol such as mannitol, or othersweeteners described herein, as a major component. For example, a candybase material may comprise from about 70 to about 98 weight percent ofthe total weight of the composition, more preferably from about 80 toabout 95 weight percent of the total weight. Lozenges often have tabletor diamond shapes, and are intended to be orally sucked on and dissolvedin the mouth of the user. The lozenge may be a hard solid or a softchew.

Buffer System

Another ingredient preferably included as part of the disclosedmedicinal delivery system is a buffering agent or system. Bufferingagents are those compounds that assist in release and conversion of thenicotine salts (ionized nicotine) to nicotine free base (unionizednicotine). Passage of actives across the mucous membranes inside themouth to the bloodstream and to target tissues is due primarily topassive diffusion of the unionized form of the active. To be effectivethe buffer agent should be released in sufficient amounts with therelease of the active to create a basic or alkaline pH environmentinside the mouth, thereby facilitating effective delivery to targetorgans. Consequently, conversion of nicotine into freebase nicotine inmouth saliva is an important step in providing smokers with adequateblood levels of nicotine to satiate cravings. Buffering agents assistwith this conversion by raising the pH and thereby facilitating nicotineabsorption.

Various salts, for example, sodium carbonate, sodium bicarbonate,potassium carbonate, potassium bicarbonate, potassium citrate anddipotassium phosphate, or mixtures thereof, are particularly preferredbuffers. Potassium carbonate alone may be especially desirable as a pHbuffering agent, especially with embodiments containing butylrubber-based gum base. The buffering agent may comprise about 0.1 weightpercent to about 10 weight percent of the nicotine delivery systemformulation, and desirably will be within the range of about 4.0 weightpercent to about 6.0 weight percent thereof. Increasing the buffer willusually result in a higher boost of pH inside the oral cavity within ashorter time period.

In one preferred embodiment of the invention, it is preferable that thebuffers be chosen so as to yield a pH in excess of at least about 7.5inside the mouth, and even more desirably in excess of about 8.0, oreven greater than about 8.5. A pH level of at least about 9.0 isparticularly preferred inside the mouth within about 10 minutes, morepreferably within about 5 minutes from the onset ofabsorption/mastication. Even more desirable is a pH of at least about9.0 within about 3 minutes, and especially within about 1 minute. Inaddition to facilitating absorption of nicotine inside the mouth, thebuffer system is preferably optimized in conjunction with the othercomponents so that it does not result in excessive, premature (i.e.,before pH adjustment by the buffer) release of nicotine inside the mouthwhich would overwhelm the user. The ideal pH level may depend on thechemical properties (e.g., pKa) of the active medicine and the desiredspeed of absorption. The quantity and type of buffer materialsfurthermore should not cause unpleasant organoleptic side effects, suchas irritation, burning, coughing or choking, etc.

Fillers

Fillers may also be present in or added to the carrier base matrix aspart of the composition of the invention. In the case of a chewing gumcarrier, the filler material optionally is selected to enhance thechewability of the final chewing gum composition. In at least someembodiments, certain filler material may also enhance the release andabsorption of nicotine and other tobacco alkaloids. Those fillers whichare substantially non-reactive with other components of the finalformulation are preferred. Desirable filler materials may includecalcium carbonate, magnesium silicate (talc), as well as dicalciumphosphate, and any mixtures thereof. Particularly preferred may bedicalcium phosphate. Other metallic mineral salts may also be utilizedas filler material, such as for example alumina, aluminum hydroxide, andaluminum silicates, provided they possess the characteristics heretoforeset forth. Filler material, when present, will typically comprise about0.1 to about 30 weight percent of the carrier base, and more preferablywill be within the range of about 10 to about 20 weight percent thereof.

Flavoring and Coloring Agents

In addition to the bulk sweetening material, the composition of theinvention also optionally comprises one or more flavoring agents. Theflavoring agents may be selected from any of the industry-availablenatural and synthetically-derived food and pharmaceutical flavors.Especially preferred are those materials which impart a cooling and/orvaporizing sensation to the consumer upon ingestion of the gum orlozenge. As non-limiting examples, peppermint, spearmint, wintergreen,cinnamon, menthol and menthone flavors, oils and derivatives aredesirable. Other compounds are contemplated as well which may impart aphysiological or psychological calming or cooling sensation to the userwho is trying to quit smoking. Those flavors which mimic the taste oftobacco are also within the scope of the invention. Food andpharmaceutical grade coloring agents available throughout the industrymay also be utilized. Any of the foregoing flavor and coloring agents,either alone or in combination will typically comprise from about 0 toabout 10 weight percent of the carrier composition, more preferably fromabout 0.1 to about 5 weight percent, and even more desirably about 2 toabout 3 weight percent of the carrier composition. It is also within thescope of the invention for the formulation to specifically omit anyadjunct flavors or colors. These embodiments may be preferred to avoidmaking the final product in any way attractive or enticing tonon-smokers and especially children.

Additives and Other Materials

Also optionally included as part of the medicinal delivery systemembodied herein is one or more of non-cariogenic, anti-cavity andtooth-whitening ingredients. These are preferably utilized with thenon-cariogenic sweeteners heretofore described. U.S. Pat. No. 5,762,911describes anti-cariogenic agents such as calcium salts, arginine and acariostatic anion such as an organic phosphate compound. Tooth-whiteningcompounds include, for example, kaolin, calcium carbonate, silicondioxide and certain cellulosic materials. These may be included in thefinal formulation in amounts of from about 0 to about 10 percent byweight, and more preferably from about 0 to about 3 weight percent.

Trace amounts of standard industry preservatives such as butylatedhydroxy toluene (BHT) may also be present in amounts less than about0.1% or so of the carrier base.

Products and Product Characteristics

An exemplary implementation of the present invention as a medicinaldelivery system is designed to permit a rapid and highly reliablerelease of active medicine inside the body and especially in the mouthand buccal cavity. While other forms may be contemplated by thoseskilled in the art and are within the scope set forth herein, themedicine delivery system is preferably in the form of a chewing gum. Itis particularly preferred that the medicated chewing gum delivery systemcomprise a chewing gum base mixed with a saliva-soluble powder coatedwith a craving-satiation compound.

The medicinal delivery system may be formulated into any desired shapeor size. Preferably, gum-based medicinal delivery systems will take theshape of sticks or tabs, or any other form, such as those which aretypically utilized by chewing gum manufacturers. Lozenges typically takethe form of tablets, but may be shaped into various objects. Eachserving may be coated with an edible confectionery-type shell.Optionally, the shell may contain a craving-satiation agent, such asnicotine, and/or any of the non-active ingredients (e.g., bufferingagent) mentioned herein.

Other possible physical embodiments of the medicinal delivery system ofthe invention include, for example, various centerfill configurations.In the center-fill embodiments the gum base or lozenge base compositionwill at least partially surround a centerfill. The centerfill may be aliquid or semi-liquid material. The centerfill material may be an activeingredient or a non-active, such as buffers, sweeteners and/orflavorants as heretofore described. A combination of saccharidematerial, flavoring, polyol and edible gel material is one example of acenterfill. The centerfill embodiments may be prepared using methodsknown in the confectionery and chewing gum industries, such as themethod described in U.S. Pat. No. 3,806,290. Other methods of formingcenterfill lozenges and chewing gum known in the art may also beutilized.

Craving Treatment and Efficacy

The delivery system of the invention can be used for a variety oftherapeutic purposes including as part of a smoking cessation orreduction program, or as a smoking alternative as in situationalcircumstances dictating abstinence, such as for satiating a craving in asmoke free environment (e.g., on a plane, public transportation,smoke-free offices, etc.). According to a contemplated treatment regime,a serving size piece of the delivery system is introduced into themouth, the user chews the gum or digests the lozenge as is normally donewith any non-medicated type of carriers for at least 5 minutes, andoptionally up to about 20 minutes to about 30 minutes or more. Chewingrate is not particularly limited, but an approximately average rate ofabout 10-30 chews per minute is contemplated. The gum is then discarded,whereas lozenges are usually dissolved in the mouth and swallowed. Thisprocess is repeated as long as nicotine cravings arise or the risk ofsmoking is present. Care should be exercised, however, to avoidoverdosing on this smoking substitute. A serving of the nicotinedelivery system of the invention is designed to cause a loaded nicotineconcentration level in the bloodstream of at least about 2 to 7nanograms of nicotine per milliliter of blood. More preferably, at leastabout 3 ng/mL nicotine will be attained, and more preferably at leastabout 5 ng/mL. If desired, the present invention can attain a nicotineconcentration of 10 ng/mL in the bloodstream.

The combination of active(s), buffer(s) and inert ingredient(s)constituting the nicotine delivery system composition of the inventiontogether result in a formulation which is highly effective as a smokingsubstitute for satiating nicotine cravings and relieving withdrawalpains. The formulations in preferred embodiments deliver at least about45%, and more preferably at least about 50% of its nicotine content in asuitable form for absorption within about 5 minutes of ingestion. Inthis way, a smoker's physiological need for the drug is sated quickly,just as would be accomplished by smoking a cigarette. In particular, asmoker generally drags more strongly on a cigarette during the initial1-2 minutes of smoking, extracting a high initial load of nicotine toquickly sate his or her physiological cravings. The nicotine-satiationsystem of the invention preferably provides an initial nicotine releaserate that is comparable to the intensity of the cigarette drag over afive minute period, thereby satiating the episodic event.

It is also preferred that subsequent to this initial rapid releasephase, the nicotine delivery system settle into a less rapid, continuousrelease for at least about an additional 10 minutes, still morepreferably at least about an additional 25 minutes. The release ofactive during this continuous phase may be relatively uniform.

Advantageously, the release of nicotine is substantially but preferablynot completely independent of the actual ingestion rate. For example, inthe case of a chewing gum base, active release will occur whether thecomposition is chewed continuously, or whether the “chew and park”method is utilized. Thus, the consumer does not have to be particularlyconscious of his/her chewing action in order to effectively receivenicotine. However, at the same time, the release rate will be affectedsomewhat by the rate of mastication. If chewers feel a continuing needfor nicotine after a number of minutes, they can chew more rapidly,whereas if they feel their cravings subsiding, they can chew moreslowly, and thereby release less nicotine. Consequently, the product isstill responsive to the needs of the chewer, who can adjust intake ofnicotine to match their cravings. The same holds true with lozenges,which can be manipulated by the tongue or sucked more vigorously by theuser to increase lozenge dissolution and increase nicotine dosing.

Without wishing to be bound by any theory, it is believed that the highinitial release rate of nicotine attainable by the present invention isdue, at least in part, to the “solvent treatment” of nicotine duringpreparation of the premix. The “solvent treatment” disperses thenicotine over the relatively large surface area of the saliva-solublepowder, making the nicotine readily available for release and absorptioninto the blood stream. It is further believed that the solvated nicotineundergoes a change in its crystalline form, perhaps transforming to anamorphous state, which is believed to further promote the release andabsorption of the nicotine. Finally, because the powder is rapidlydissolved in saliva, it provides a fluid medium for entraining andcarrying the nicotine or other active out of the gum for absorption bythe chewer.

Rate of nicotine release may be measured using the following procedure.Individual, weighed pieces of the nicotine release system (e.g., gum)are chewed by participants either ad lib (at the participant's preferredchew rate) or at a scheduled rate (e.g., using a metronome). Individualpre-weighed pieces are chewed or digested for a predetermined time(e.g., 3, 5, 10, 20, 30 minutes) while timing with a stop watch. At theconclusion of the designated periods, the samples are placed in glassvials and labeled. Chewers are instructed to drink water betweensessions to cleanse their palates. No eating or drinking is allowedduring the chewing session. The samples are stored in arefrigerator/freezer. Nicotine content in residual gum is measured usinga validated high performance liquid chromatography (HPLC) method. Thepercent dose (normalized to weight) of nicotine released at each timeinterval is determined by subtraction of residual nicotine remaining inthe gum from the starting amount.

While the invention has been described with particular reference tosmoking reduction or cessation, it is also within the scope hereof thatthe nicotine delivery system heretofore described also be utilized inthe treatment of certain diseases as well. For example, studies havedemonstrated that nicotine therapy can be particularly beneficial topersons with ulcerative colitis, Parkinson's disease, Tourette'ssyndrome and Alzheimer's disease as well.

EXAMPLES

The following examples are provided to elaborate upon the principals ofthe invention and are not intended to limit the scope of the invention.Tables 2, 4, and 6 set forth the compositions of various examples andcomparative examples of medicated chewing gum compositions, with each ofTables 2, 4, and 6 reporting concentrations in percent by weight basedon the total weight of the composition. Tables 3, 5, and 7 set forth thepremix compositions for the examples and comparative examples of Tables2, 4, and 6, respectively. Tables 3, 5, and 7 report premixconcentrations based on parts by weight for the premix composition only.Tables 8-10 set forth the results of release measurement experiments foreach of the examples and comparative examples, reporting the percentdose of nicotine released as a function of time (in minutes). Theseresults are based on humans chewing the example gums at a chew rate ofevery 2 seconds. These results are reported as the mean % dose ofnicotine release across three participants.

Example 1

4.40 mg of nicotine bitartrate dihydrate (NBD) was added to 70% sorbitolsolution and stirred until the NBD partially dissolved into a whitepaste. The NDB solution was allowed to sit for several minutes. Sorbitolpowder was added into a high speed food processor, then the NBD solutionwas added to form a premix. The premix was added to the gum formulation.

Example 2

Repeat procedures of Example 1, except at concentrations set forth forExample 2 in Table 2. The mixing of sorbitol solution and NBD solutionwas conducted for about 4 minutes, and the premix was screened beforebeing added to the gum formulation.

Example 3

Repeat procedures of Example 1, except at concentrations set forth forExample 3 in Table 2.

Example 4

Repeat procedures of Example 1, except at concentrations set forth forExample 4 in Table 2. Water replaced sorbitol solution duringpreparation of the premix composition, and was evaporated off in an ovenafter premix was formed.

Example 5

Repeat procedures of Example 1, except at concentrations set forth forExample 5 in Table 2. Ethanol replaced the sorbitol solution duringpreparation of the premix composition, and was evaporated off after thepremix was formed.

Example 6

Repeat procedures of Example 1, except at concentrations set forth forExample 6 in Table 2. Ethanol replaced the sorbitol solution duringpreparation of the premix composition.

Example 7

Repeat procedures of Example 5, except at concentrations set forth forExample 7 in Table 2. Ethanol was not evaporated off. Premix wasscreened before being added to the gum formulation.

Example 8

Repeat procedures of Example 5, except at concentrations set forth forExample 8 in Table 2. Ethanol was evaporated from the premix.

Example 9

Repeat procedures of Example 5, except at concentrations set forth forExample 9 in Table 2. Ethanol was not evaporated off.

Example 10

Repeat procedures of Example 5, except at concentrations set forth forExample 10 in Table 2. Ethanol was not evaporated off.

Example 11

Repeat procedures of Example 1, except at concentrations set forth forExample 11 in Table 4, and ethanol replaced the sorbitol solution duringpreparation of the premix composition.

Example 12

Repeat procedures of Example 1, except at concentrations set forth forExample 12 in Table 4.

Example 13

Repeat procedures of Example 1, except at concentrations set forth forExample 13 in Table 4. Ethanol replaced the sorbitol solution duringpreparation of the premix composition.

Example 14

Repeat procedures of Example 1, except at concentrations set forth inTable 4, and replace sorbitol solution with water as the solvent duringpreparation of the premix composition. Water was not evaporated frompremix.

Example 15

Repeat procedures of Example 1, except at concentrations set forth inTable 4, and replace sorbitol solution with water as the solvent duringpreparation of the premix composition. Water was evaporated from premix,and the premix was screened prior to being added to the gum formulation.

Comparative Examples 16-26

Repeat procedures of Example 1, except at concentrations set forth forthe comparative examples in Tables 4 and 6.

Comparative Example 27

No premix was added to the gum formulation, which included 0.67% NBDadded directly to the sorbitol powder in the mixer.

TABLE 2 Gum compositions (pbw total composition; Examples 1-10) Gumexample # 1 2 3 4 5 6 7 8 9 10 Nicotine input (mg) 4.40 2.20 2.20 2.202.20 2.20 2.20 2.20 2.20 2.20 NTI gum base 40.00 40.00 40.00 40.00 32.0040.00 32.00 40.00 45.00 40.00 Lycasin (85%) 10.00 10.00 Sorbitol 60W29.05 29.05 29.05 29.05 27.05 27.55 27.05 19.05 14.05 19.05 Potassiumcarbonate 4.50 4.50 4.50 4.50 4.50 6.00 4.50 4.50 4.50 4.50 Sucralose0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 Acesulfame K 0.20 0.200.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 Menthol crystals 0.65 0.65 0.650.65 0.65 0.65 0.65 0.65 0.65 0.65 Super intense cooling mint flavor2.58 2.58 2.58 2.58 2.58 2.58 2.58 2.58 2.58 2.58 Spearmint flavor 0.720.72 0.72 0.72 0.72 0.72 0.72 0.72 0.72 0.72 Spray dried peppermintpowder 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 Premix 20.0020.00 20.00 20.00 20.00 20.00 20.00 30.00 30.00 30.00

TABLE 3 Premix compositions (pbw premix; Examples 1-10) Gum example # 12 3 4 5 6 7 8 9 10 Sorbitol soltn (70%) 15.00 10.00 5.00 Water 6.8Ethanol 20.00 20.00 20.00 26.00 26.00 26.00 Sorbitol powder 78.06 86.6291.62 96.62 76.62 76.62 76.62 97.75 97.75 97.75 Mannitol NBD 6.69 3.383.38 3.38 3.38 3.38 3.38 2.25 2.25 2.25 Yellow No. 10 0.25

TABLE 4 Gum compositions (pbw total composition; Examples 11-16 andComparative Examples 17-20) Gum example # 11 12 13 14 15 16 17 18 19 20Nicotine input (mg) 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20NTI gum base 40.00 45.00 45.00 40.00 40.00 40.00 40.00 35.00 40.00 MagnaT gum base 27.50 Nova T gum base 27.50 Lycasin (85%) 10.00 Sorbitol 60W29.05 34.05 39.05 29.05 29.05 39.05 29.05 24.05 19.05 29.05 Potassiumcarbonate 4.50 4.50 4.50 4.50 4.50 4.50 4.50 4.50 4.50 4.50 Sucralose0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 Acesulfame K 0.20 0.200.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 Menthol crystals 0.65 0.65 0.650.65 0.65 0.65 0.65 0.65 0.65 0.65 Super intense cooling mint flavor2.58 2.58 2.58 2.58 2.58 2.58 2.58 2.58 2.58 2.58 Spearmint flavor 0.720.72 0.72 0.72 0.72 0.72 0.72 0.72 0.72 0.72 Spray dried peppermintpowder 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 2.20 Premix 20.0010.00 5.00 20.00 20.00 10.00 20.00 20.00 30.00 5.00

TABLE 5 Premix compositions (pbw premix; Examples 11-16 and ComparativeExamples 17-20) Gum example # 11 12 13 14 15 16 17 18 19 20 Sorbitolsoltn (70%) 10.00 Water 6.80 6.8 Ethanol 20.00 15.00 10.00 Sorbitolpowder 76.62 52.16 50.85 96.62 89.82 91.62 96.62 97.75 57.52 Mannitol26.08 25.43 83.31 28.76 NBD 3.38 6.76 13.72 3.38 3.38 6.69 3.38 3.382.25 13.72 Lycasin (75%) 5.00

TABLE 6 Gum compositions (pbw total composition; Comparative Examples21-27) Gum example # 21 22 23 24 25 26 27 Nicotine input (mg) 2.20 2.202.20 2.20 2.20 2.20 2.20 NTI gum base 45.00 35.00 45.00 55.00 40.00 NovaT gum base 55.00 Dreyco gum base 55.00 Sorbitol 60W 29.05 29.05 34.0548.48 37.55 29.05 46.38 Potassium carbonate 4.50 4.50 4.50 6.00 6.004.50 4.50 NBD 0.67 Glycerin 5.00 Sucralose 0.10 0.10 0.10 0.10 0.10 0.100.10 Acesulfame K 0.20 0.20 0.20 0.20 0.20 0.20 0.20 Menthol crystals0.65 0.65 0.65 0.55 0.65 0.65 0.65 Super intense 2.58 2.58 2.58 2.192.58 2.58 2.58 cooling mint flavor Spearmint flavor 0.72 0.72 0.72 0.610.72 0.72 0.72 Spray dried pepper- 2.20 2.20 2.20 1.87 2.20 2.20 2.20mint powder Premix 5.00 5.00 5.00 5.00 5.00 5.00 0.00

TABLE 7 Premix compositions (pbw premix; Comparative Examples 21-27) Gumexample # 21 22 23 24 25 26 27 Sorbitol solution N/A Sorbitol powder57.52 57.52 57.52 57.69 57.52 N/A Mannitol 28.76 28.76 28.76 28.85 28.72N/A NBD 13.72 13.72 13.72 13.46 13.72 N/A

TABLE 8 Nicotine Release (percent dose) (ND = not determined) Time (min)1 2 3 4 5 6 7 8 9 10 1 38 35 ND ND ND ND 23 ND ND ND 3 47 47 47 ND 39 4234 40 37 40 5 52 53 58 54 50 48 43 45 45 47 10 64 66 74 72 65 64 59 5960 58 20 ND ND ND ND ND ND ND ND ND ND 30 84 ND ND ND ND 83 ND ND ND ND

TABLE 9 Nicotine Release (percent dose) (ND = not determined) Time (min)11 12 13 14 15 16 17 18 19 20 1 ND ND ND ND 20 18 ND ND ND ND 3 40 35 3238 31 31 31 38 27 25 5 49 43 43 45 40 40 38 44 35 35 10 63 55 59 64 5553 53 55 48 62 20 ND 73 74 ND ND ND ND ND ND ND 30 86 86 84 ND ND 83 NDND ND 89

TABLE 10 Nicotine Release (percent dose) (ND = not determined) Time(min) 21 22 23 24 25 26 27 1 ND ND ND ND ND ND 19 3 19 18 31 33 27 26 295 30 26 37 44 34 32 36 10 57 42 51 52 49 47 52 20 ND ND ND 66 59 66 ND30 82 73 81 ND ND 79 81

Each of Examples 1-3 containing sorbitol solution as a solvent exhibitedan initial release rate of greater than 50 weight percent within 5minutes of mastication followed by slower release over the remainingperiod of chewing. Example 4, which used a water solvent, had excellentrelease rate results but lesser uniformity of distribution than Examples1-3, which utilized sorbitol solution as the solvent. FIG. 2demonstrates in graphical format the differences between nicotinerelease rate between Example 1 (52 wt % release at 5 minutes) versusComparative Example 26 (32 wt % release at 5 minutes), which did notinclude a solvent. By way of further comparison, but not illustrated inFIG. 2, Comparative Example 27 (no premix) had a release rate of 36 at 5minutes.

FIG. 3 illustrates in graphical format the release rates of Examples 2and 7 and Comparative Example 26. Example 2 using a sorbitol solutionsolvent produced a release rate of 53 at 5 minutes. Example 7 had a lesseffective yet efficient release of 43 weight percent at 5 minutes. Eachof these release rates was more than 10 weight percent greater than thatof Comparative Example 26 over the same 5-minute time interval.

FIG. 4 illustrates a graph of the release rates of Examples 5, 6, and 14and Comparative Example 26. The release rates of the examples were allat or above about 45 weight percent at 5 minutes, more than 10 weightpercent greater than Comparative Example 26.

The following observations were also made. The inclusion of ethanol as asolvent in Examples 12 and 13 produced an improvement of about 8 wt % inrelease rate compared to similarly formulated Comparative Example 25,which did not contain ethanol or another solvent.

Examples 8-10, which were characterized by the partial dissolution ofnicotine in ethanol to provide a white dispersion at room temperature,produced release rates that exhibited an improvement of 10 wt % or moreat t=5 minutes compared to similarly formulated Comparative Example 19,which was free of solvent.

It is believed that Example 16, which included sorbitol solution, wasnot as effective as other examples because the premix containedmannitol, which did not hydrate as fast as sorbitol would in the gumduring chewing. Similarly, it is believed that the reduced release ratesof Examples 12 and 13 (43 each) was attributable to the presence of theless soluble mannitol in the premix.

Examples 28 and 29

Additional exemplary chewing gum compositions are set forth in Table 11below, and premix compositions are set forth in Table 12 below. For eachof examples 28 and 29, sorbitol powder and yellow color were mixed in afood processor (or other high speed mixer) at low setting for 1 minuteat concentrations set forth for the comparative examples in Tables 11and 12. In a stainless steel container, NBD was added to sorbitolsolution (70%) and mixed by hand with a spatula for 1 minute. Thenicotine/sorbitol solution mixture was slowly added to thesorbitol/color mix in the food processor and mixed for 4 minutes at lowsetting. The resulting premix composition was screened through a 10 mesh(2000 microns) stainless steel screen. The premix was added to the gumformulation.

TABLE 11 Gum compositions (pbw total composition; Examples 28 & 29) Gumexample # 28 29 Nicotine input (mg): 4.00 4.00 Gum Base: Butyl rubber2.600 3.575 BHT 0.024 0.033 Ester 5 4.160 5.720 Soybean Oil, PartiallyHydrogenated 7.236 9.950 Polyisobutylene 3.600 4.950 DicalciumPhosphate, Anhydrous, USP 8.180 11.247 (Powder) Polyvinyl Acetate 9.60013.200 Wax, Microcrystalline 2.000 2.750 Mono And Diglycerides 2.6003.575 Excipients, Buffer, Active: Sorbitol 60W 29.050 29.050 AcesulfameK 0.200 0.200 Sucralose, Micronized 0.100 0.100 Potassium Carbonate,Extra Fine 4.500 4.500 Anhydrous Flavor System: Cooling mint flavor2.580 2.580 Menthol Crystals 0.650 0.650 Peppermint Flavor, Spray Dried2.200 2.200 Spearmint Oil 0.720 0.720 Premix 20.000 5.000

TABLE 12 Premix compositions (pbw premix; Examples 28 and 29) Gumexample # 28 29 Sorbitol solutn (70%) 3.000 NBD 1.356 1.359 Sorbitolpowder 15.594 2.394 Mannitol powder 1.197 Yellow No. 10 0.050 0.050

Processing aids used during mixing of gum examples 28 and 29 includedtalc and sterile water.

Examples 28, 29, and NICORETTE® FreshMint (4 mg) were evaluated in asingle dose, randomized, crossover bioavailability pilot study. Thestudy's primary objective was to compare the plasma nicotine absorptionof a single 4 mg dose of Example 28 relative to a single 4 mg dose ofExample 29 and a single 4 mg dose of NICORETTE gum within the first 10minutes of dosing (i.e., AUC₀₋₁₀) in healthy adult smokers. The testgroup consisted of 14 individuals between the ages of 20 and 40, 64%male and 36% female, median age 26. The test group averaged 10cigarettes per day (11.6±6.2), and 5.5 years as the median number ofyears smoked (9.1±7.9). Nicotine plasma concentration levels were thentested at specified time intervals. Baseline-adjusted plasma levels ateach time interval was calculated using the following formula:C_(T)(adj)=C_(T)−[C⁻⁵−C⁻⁵e^(−Kt)], wherein K=0.693/t_(1/2), t=timepoint,and t_(1/2)=nicotine half-life. Mean plasma concentration data for rawdata and adjusted baseline data are provided in Table 13 below:

TABLE 13 (Mean nicotine plasma concentration data for examples 28, 29 &NICORETTE) RAW BASELINE ADJUSTED Time Std Std Example # (minutes) N MeanDev N Mean Dev 28 0 14 4.76 2.64 14 0.00 0.00 2 14 5.34 2.80 13 0.661.09 4 14 7.57 4.45 13 2.74 4.24 6 13 8.62 4.69 13 3.89 3.98 8 13 10.244.63 13 5.56 4.47 10 13 11.40 4.34 13 6.78 4.33 15 14 13.58 4.37 13 9.154.05 30 14 15.63 4.85 13 11.76 4.28 45 14 17.75 7.10 13 14.27 6.17 60 1417.75 7.28 13 14.57 6.22 90 14 16.66 7.12 13 13.83 6.39 180 14 11.996.36 13 10.36 6.03 29 0 14 4.72 3.42 14 0.00 0.00 2 14 4.77 3.27 14 0.480.83 4 13 5.15 2.85 14 0.76 0.92 6 13 6.27 2.73 14 1.73 1.78 8 14 7.663.17 14 3.40 2.84 10 14 8.21 3.57 14 3.96 3.78 15 14 10.75 4.22 14 6.544.54 30 14 13.56 3.96 14 9.70 4.62 45 14 14.68 5.22 14 11.14 4.59 60 1415.11 5.87 14 11.87 4.94 90 14 13.07 5.64 14 10.34 4.71 180 14 9.15 4.0114 7.53 3.41 NICORETTE 0 13 4.92 4.42 13 0.00 0.00 FreshMint 2 14 5.504.68 13 0.32 0.43 4 14 5.31 4.56 13 0.21 0.26 6 13 5.59 4.53 13 0.500.51 8 14 6.12 4.38 13 1.10 1.10 10 14 6.94 4.67 13 1.93 1.77 15 14 9.045.35 13 3.86 2.03 30 14 13.55 5.49 13 8.64 3.57 45 14 15.87 6.25 1311.03 2.88 60 14 16.57 8.20 13 11.40 2.57 90 14 14.61 7.41 13 10.31 2.98180 14 10.42 6.19 13 7.60 3.37

FIG. 5 demonstrates in graphical format the mean plasma concentrationsof examples 28, 29 and NICORETTE in ng/mL, based on data from timeintervals of 0, 2, 4, 6, 8, 10, 15, 30, 45, 60, 90 and 180 minutes. Rawdata baseline is −5 minutes; adjusted data baseline is 0 minutes. Fromtime −5 minutes to 10 minutes is also shown in graphical format in FIG.6. At 4 minutes, example #28 achieved a nicotine plasma concentrationsubstantially higher than either example #29 or the comparativeNICORETTE example.

Mean pharmacokinetic parameter estimates for raw plasma concentrationdata and for baseline adjusted plasma concentration data were calculatedusing area under the curve (AUC) calculations, such as disclosed byRowland M, Tozer T N, Clinical Pharmacokinetics: Concepts andApplications, Lea & Febiger, Philadelphia, p. 21 (1989), the disclosureof which is incorporated herein by reference. Pharmacokinetic parameterestimates based on raw data are provided in Table 14 below.Pharmacokinetic parameter estimates based on baseline adjusted data areprovided in Table 15 below. As can be seen in Tables 14 and 15, the meanAUC₀₋₁₀ for Example 28 was significantly greater than the NICORETTEexample. These results indicate that plasma nicotine levels weresignificantly greater for Example 28 than NICORETTE during the first 10minutes of chewing. Similarly, Example 28 delivered significantly morenicotine compared to Example 29 and the NICORETTE example during thefirst 90 minutes of plasma sampling and during the entire 180 minutes ofplasma sampling.

TABLE 14 (Parameter Estimates from raw data for examples 28, 29 &NICORETTE in ng/mL*minutes) Mean (±S.D.) Pharmacokinetic ParameterEstimates - Raw Plasma Concentrations Example 28 Example 28 Example 29v. v. v. NICORETTE Example 29 NICORETTE NICORETTE Measure Example 28Example 29 FreshMint (p values) (p values) (p values) AUC₀₋₁₀(trapezoidal) 79.69 ± 36.54  59.93 ± 27.25  52.20 ± 42.56 0.0857 0.03420.6167 AUC₀₋₁₀ (log transformed) 72.32 ± 1.60  53.98 ± 1.64 40.58 ± 2.070.0895 0.0036 0.1372 AUC₀₋₉₀ (trapezoidal) 1410.06 ± 522.87  1147.56 ±388.72 1090.93 ± 403.85 0.0079 0.0110 0.9478 AUC₀₋₉₀ (log transformed)1323.09 ± 1.46   1089.97 ± 1.39  1036.9 ± 1.37  0.0125 0.0106 0.8822AUC₀₋₁₈₀ (trapezoidal) 2707.72 ± 1141.58 2147.33 ± 804.37 2100.79 ±832.93 0.0021 0.0113 0.5411 AUC₀₋₁₈₀ (log transformed) 2502.00 ± 1.51  2023.48 ± 1.42  1981.84 ± 1.40  0.0030 0.0097 0.6820 C_(max) 19.62 ±7.29  16.07 ± 5.75 15.75 ± 4.81 0.0085 0.0250 0.6859 T_(max) 53.08 ±15.75  47.14 ± 19.39  55.38 ± 15.47 0.4653 0.7226 0.2801

TABLE 15 (Parameter Estimates from baseline adjusted data for examples28, 29 & NICORETTE in ng/mL*minutes) Mean (±S.D.) PharmacokineticParameter Estimates - Baseline Adjusted Plasma Concentrations Example 28Example 28 Example 29 v. v. v. NICORETTE Example 29 NICORETTE NICORETTEMeasure Example 28 Example 29 FreshMint (p values) (p values) (p values)AUC₀₋₁₀ (trapezoidal)  32.49 ± 30.24  16.70 ± 13.96 6.17 ± 5.07 0.02620.0011 0.1716 AUC₀₋₁₀ (log transformed) 23.29 ± 2.32 11.03 ± 2.95 4.23 ±2.65 0.0533 0.0001 0.0161 AUC₀₋₉₀ (trapezoidal) 1066.60 ± 417.39  826.98± 329.17 755.77 ± 183.20 0.0079 0.0054 0.8103 AUC₀₋₉₀ (log transformed)998.65 ± 1.46  769.58 ± 1.48  734.64 ± 1.29  0.0180 0.0157 0.9028AUC₀₋₁₈₀ (trapezoidal) 2155.43 ± 958.92 1631.12 ± 657.32 1561.86 ±419.30  0.0007 0.0029 0.6277 AUC₀₋₁₈₀ (log transformed) 1988.06 ± 1.51 1525.79 ± 1.45  1512.00 ± 1.30   0.0018 0.0081 0.5870 C_(max) 16.03 ±6.20 12.77 ± 5.17 12.37 ± 2.72  0.0116 0.0231 0.8124 T_(max)  53.08 ±15.75  50.36 ± 17.26 58.85 ± 16.73 0.7058 0.4020 0.2240

While this invention has been described as having a preferred design, itis understood that it is capable of further modifications, uses and/oradaptations of the invention, following in general the principle of theinvention and including such departures from the present disclosure ascome within known or customary practice in the art to which theinvention pertains, and as may be applied to the central featureshereinbefore set forth, and fall within the scope of the invention ofthe limits of the appended claims.

What is claimed is:
 1. A method of making an orally administrablemedicinal delivery system, comprising: at least partially dissolving anicotine compound in a bulk sweetener solution comprising a solvent anda first bulk sweetener; subsequent to said at least partiallydissolving, coating the nicotine compound and the first bulk sweeteneron a saliva-soluble bulk sweetener powder comprising a second bulksweetener to establish a coated powder premix; and subsequent toestablishing the coated powder premix, combining the coated powderpremix with a chewing gum base and a buffer.
 2. The method of claim 1,wherein the nicotine compound comprises nicotine, nor-nicotine,lobeline, free base nicotine, a pharmacologically acceptable salt ofnicotine, or a combination thereof.
 3. The method of claim 1, whereinthe nicotine compound comprises nicotine hydrogen tartrate, nicotinebitartrate dihydrate, nicotine hydrochloride, nicotine sulfate, nicotinecitrate, nicotine zinc chloride monohydrate, nicotine salicylate,nicotine polacrilex, or a combination thereof.
 4. The method of claim 1,wherein first bulk sweetener comprises sorbitol, xylitol, or acombination thereof.
 5. The method of claim 1, wherein the second bulksweetener comprises sorbitol, xylitol, mannitol, isomalt, maltitol,lactitol, or a combination thereof.
 6. The method of claim 1, whereinthe first and second bulk sweeteners comprise sorbitol, xylitol, or acombination thereof.
 7. The method of claim 1, wherein the nicotine andthe first bulk sweetener are in the form of a paste when coated on thesaliva-soluble bulk sweetener powder.
 8. The method of claim 1, whereinthe medicinal delivery system provides for about 45% or more release ofthe nicotine compound within 5 minutes of the onset of ingestion ormastication.
 9. The method of claim 1, wherein the medicinal deliverysystem provides for about 50% or more release of the nicotine compoundwithin 5 minutes of the onset of ingestion or mastication.
 10. Themethod of claim 1, wherein the medicinal delivery system comprises thenicotine compound in an amorphous state dispersed on a surface of thesaliva-soluble bulk sweetener powder.
 11. A method of making an orallyadministrable medicinal delivery system, comprising: at least partiallydissolving a nicotine compound in a bulk sweetener solution comprising asolvent and a first bulk sweetener; subsequent to said at leastpartially dissolving, coating the nicotine compound and the first bulksweetener on a saliva-soluble bulk sweetener powder comprising a secondbulk sweetener to establish a coated powder premix; and subsequent toestablishing the coated powder premix, combining the coated powderpremix with a lozenge base and a buffer.
 12. The method of claim 11,wherein the nicotine compound comprises nicotine, nor-nicotine,lobeline, free base nicotine, a pharmacologically acceptable salt ofnicotine, or a combination thereof.
 13. The method of claim 11, whereinthe nicotine compound comprises nicotine hydrogen tartrate, nicotinebitartrate dihydrate, nicotine hydrochloride, nicotine sulfate, nicotinecitrate, nicotine zinc chloride monohydrate, nicotine salicylate,nicotine polacrilex, or a combination thereof.
 14. The method of claim11, wherein first bulk sweetener comprises sorbitol, xylitol, or acombination thereof.
 15. The method of claim 11, wherein the second bulksweetener comprises sorbitol, xylitol, mannitol, isomalt, maltitol,lactitol, or a combination thereof.
 16. The method of claim 11, whereinthe first and second bulk sweeteners comprise sorbitol, xylitol, or acombination thereof.
 17. The method of claim 11, wherein the nicotineand the first bulk sweetener are in the form of a paste when coated onthe saliva-soluble bulk sweetener powder.
 18. The method of claim 11,wherein the medicinal delivery system provides for about 45% or morerelease of the nicotine compound within 5 minutes of the onset ofingestion or mastication.
 19. The method of claim 11, wherein themedicinal delivery system provides for about 50% or more release of thenicotine compound within 5 minutes of the onset of ingestion ormastication.
 20. The method of claim 11, wherein the medicinal deliverysystem comprises the nicotine compound in an amorphous state dispersedon a surface of the saliva-soluble bulk sweetener powder.